The proposed K23 career development award aims to train a promising candidate to become an independent investigator in neuroimaging, genetics, and mood disorders while characterizing neurobiological mechanisms that underlie genetic risk for depression. Candidate. The candidate's education and training have prepared him well for this project. His interest in neuroscience emerged as an undergraduate at the University of Washington, where he majored in Physics and Biology. He subsequently earned his MD and PhD in Neuroscience at the University of Michigan. For his thesis project, he employed electrophysiology and computational techniques to study activity in the cerebral cortex that underlies sound perception, and in a related study, he investigated auditory processing in schizophrenia. He continued his training in psychiatry residency and fellowship at the University of Michigan, during which he was introduced to functional neuroimaging and the neurobiology of mood disorders. He was recently appointed Assistant Professor of Psychiatry at the University of Michigan. As a trained neuroscientist and psychiatrist, he is well positioned for a career in patient-oriented psychiatric neuroscience research. To achieve full research independence, he has identified three key Training Objectives: (1) experience directing a translational neuroscience research study on affective disorders, (2) training in the design, execution, and analysis of functional magnetic resonance imaging (fMRI) experiments, and (3) development of methodological expertise in molecular genetics. Environment. The proposed K23 project will take place within the Department of Psychiatry and the Molecular & Behavioral Neuroscience Institute at the University of Michigan. The Department and Institute benefit from close collaborative relationships with other units including Bioengineering, Psychology, Radiology, and the CTSA-funded Michigan Institute for Clinical and Health Research. This vigorous research environment includes ample access to fMRI facilities, genotyping resources, and clinical samples, and it nurtures an expanding group of translational psychiatric researchers. The primary mentor, Jon-Kar Zubieta MD PhD, is a productive and well-funded neuroscientist who has more than 15 years of experience with neuroimaging and genetics, and an established track record of mentoring junior investigators, including three recent K awardees. The candidate will also benefit from two local co-mentors, geneticist Margit Burmeister PhD and MRI physicist Robert Welsh PhD, and three carefully chosen consultants. Research. The K23 project focuses on neurobiological vulnerability to major depressive disorder (MDD), a common, debilitating, recurrent brain illness, and a significant public health problem worldwide. MDD is thought to arise from the interaction of environmental and genetic factors within multiple neural pathways, but progress has been hindered by our limited understanding of circuit-level endophenotypes in humans. Our recent findings implicate functional genetic variation of neuropeptide Y (NPY) in negative emotional processing and risk for MDD, suggesting a way forward. While NPY has been consistently implicated in avoidance behavior and circuitry, preclinical data have also indicated a role in approach behavior and circuitry (reward, motivated behavior, and appetitive drive). Our preliminary fMRI data suggest that NPY influences approach circuitry in humans as well, specifically implicating ventral striatum, medial prefrontal cortex, and the interaction of these regions. The impact of NPY variation on approach circuitry and functional connectivity deserves further investigation. Specific Aim 1: NPY genotyping, plasma NPY, and behavioral characterization. We propose to recruit 240 healthy participants and classify them by NPY genotype. We will characterize the effects of NPY variation on plasma NPY levels, motivated behavior, and emotional traits. (Aligns with Training Objectives 1 and 3.) Specific Aim 2: Effects of NPY on reward circuitry and connectivity. We will characterize NPY effects on reward processing and functional connectivity in healthy participants classified as low- or high-expression (n=30 per group). We will test whether NPY influences (i) activation of reward circuitry differentially during processing of monetary loss versus gain and (ii) patterns of functional connectivity at rest. (Aligns with Training Objective 2.) Summary. The proposed K23 award is well aligned with the missions of the NIH and PHS. The project will train a promising early investigator to become a clinical translational neuroscientist. At the same time, the project will address important, testable questions about the neurobiology of genetic vulnerability to MDD, an identified public health priority. PUBLIC HEALTH RELEVANCE: The proposed K23 project serves dual purposes: (1) to train a promising physician-scientist to become an independent investigator in brain imaging, genetics, and mood disorders, and (2) to characterize brain mechanisms that underlie genetic risk for depression. Accomplishment of these two objectives will address the recognized shortage of physician scientists that are pursuing translational research, and simultaneously answer clinically relevant questions about a common, disabling brain illness that too often fails to respond to current treatments.